Hydrolysis of 3, 20-diacyloxy-9 (11), 17 (20)-dioxido-5, 7-pregnadiene adducts



Patented Aug. 17, 1954 HYDROLYSIS OF 3,20-DIACYLOXY- 9(11),17(20)DIOXIDO 5,7 PREG- NADIENE ADDUCTS Robert H. Levin and George B. Spero,Kalamazoo Township, Kalamazoo County, andA. Vern McIntosh, Jr.,Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a

corporation of Michigan N Drawing. Application February 3, 1953,

SerialNo. 334,966

Claims. (01. 260-23955) The present invention relates to the hydrolysisof certain adducts of 3,20-diacyloxy-9(ll) ,17-(20)-dioXido-5,7-pregnadiene, and to the products thusproduced.

The compounds of the present invention may be representedby thestructural formula:

=0 CHI 1.--. 11

wherein Ac is hydrogen or the acyl radical of an organic carboxylicacid, especially such acids containing from one to eight carbon atoms,inclusive; and A is an adduct radical derived from a dienophile selectedfrom the group consisting of maleic acid, maleic anhydride andmaleicacid diesters containing from one to eight carbon atoms, inclusive, inthe esterifying group.

It is an object of the present invention to provide a novel group ofcompounds which are useful in the preparation of steroid compoundscontaining an oxygen atom at carbon atom eleven. Another object of theinvention is the provision of a process for the production of the novelcompounds, adducts of S-hydroxy and B-acyloxy- 9(11) -oxido-17 hydoxy5,7 pregnadiene 20- ones. Other objects of the invention will beapparent to one skilled in the art to which this invention pertains.

The compounds of the present invention, as

described previously in application Serial Number 265,542, nowabandoned, filed January 8, 1952, of which this is acontinuation-in-part, are useful in the preparation of steroid compoundshavingan oxygen atom attached to carbon atom eleven. Such compounds areof particular interest in the field of steroid research due to thebiological activity of the cortical hormones. For example,3,17a-dihydroxy-9(11) -oxido-5,7- pregnadiene-20-one dimethyl maleateadduct (claim 2) may be converted. to cortisone or cortisone acetate bythe following steps: hydrolysis with sodium hydroxide to give3,17oc,9,'11- tetrahydroxy-5,7-pregnadiene 20 one disodium maleateadduct, oxidation with chromic acid and Clemmenson reduction Icf.Fieser, J. Am. Chem.

Soc. 72, 2306 (1950)] to give the lia-hydroxy-5,7-pregnadiene-3,11,20-trione disodium maleate adduct, treatment with adilute mineral acid to give 17 hydroxy 5,7 pregnadiene 3,11,20- trionemaleic acid adduct, pyrolysis of the adduct (cf. Levin et 9.1., U. S.Patent 2,588,396 issued March 11, 1952) to give17a-hydroxy-5fl-pregnadiene-3,11,20-trione, hydrogenation to give 17cchydroxypregnane 3,11,20 trione and17ahydroxyallopregnane-B,11,20-trione, both known compounds. 17ozHydroxypregnane' 3,11,20- trione was used as an intermediate in thepreparation of cortisone and cortisone acetate by Kritchevsky, Garmaiseand Gallagher, J. Am. Chem. Soc. 74, 483 (1952).l'lu-hydroxyallopregnane-3,11,20-trione can also be converted tocortisone acetate by reduction with sodium borohydride to3a,17u-dihydroxyallopregnane- 11,20-dione which can be brominated in the21- position, then converted with potassium acetate to 3a,17a dihydroxy21 acetoxyallopregnane- 11,20-dione and oxidized with chromic acid tol'la-hydroxy 21 acetoxyallopregnane 3,11,20- trione, a known compoundwhich Djerassi, Nature 168, 28 (1951) transformed into cortisoneacetate. Novel compounds of the present invention which are ofparticular interest are those compounds of the above generic formulawherein Ac represents hydrogen or the acyl radical of an organiccarboxylic acid containing up to and including eight carbon atoms. Amongthe acids which can be used are the aliphatic, cycloaliphatic and arylillustrated by formic, acetic, propionic, e-cyclopentylpropionic,butyric, isobutyric, valeric, isovaleric, hexanoic, heptanoic, octanoic,succinic, glutaric, cyclopentanoic, cyclohexanoic, benzoic, toluic,phenylacetic, and the like. Preferred acids are the lower-aliphaticacids. The acids may also contain substituents, such as halo, alkyl, andmethoxy, which are non-reactive under the reaction conditions employed.The adduct bridge (-A-) in such compounds may be represented by thegraphic formula:

(E-COQR wherein R. represents the organic residue of an alcohol. Suchesters include the methyl, ethyl,

propyl, isopropyl, butyl, isobutyl, lauryl, heptyl, octyl, cyclopentyl,cyclohexyl, benzyl, and like esters. The esterifying radical may alsocontain non-reactive substituents, such as halo, methoxy, or hydroxy, ifdesired. While the esters of the maleic acid adduct are described hereinwith particular reference to the methyl esters, the preferred embodimentof R is a loweralkyl radical containing from one to eight carbon atoms,inclusive. Alternatively, the adduct radical may be depicted by thegraphic formula:

which is representative of the maleic anhydride adduct.

The compounds of the invention are usually colorless crystalline solids,which are soluble in ether, halogenated hydrocarbons, acetone, ethylacetate, and benzene.

In carrying out the process of the present invention, the hydrolysis of3,20-diacyloxy-9(ll) 1'7(20)-dioxide-5,'7-pregnadene adducts isconveniently accomplished in an organic solvent such as, forexample,methanol, ethanol, acetone, dioxane, benzene or toluene in a two-phasesystem, and the like, methanol being preferred, with a saponifyingagent. The preferred saponifying agent is sodium hydroxide, butotherbases such as, for example, sodium carbonate, sodium bicarbonate,potassium hydroxide, and the like are operative. The adduct is generallydissolved in the desired solvent and an aqueous solution of the desiredbase is added thereto. Usually about one hour at room temperature is asufficient length of time to complete the reaction, but temperatures ofbetween about zero and about sixty degrees centigrade, or even higher orlower, are operative. The time needed to complete the reaction isgenerally dependent on the adduct used and the temperature employed, thehigher temperatures requiring less time for completion of the reaction.Any period of time between about a few minutes and several hours may beutilized. After the reaction is complete, the product may be isolated inany convenient manner such as, for example, drowning out with water andextracting with a solvent such as ether, chloroform or benzene, and thelike. The residue obtained after removal of the solvent may then becrystallized, if desired, from any organic solvent, with a mixture ofacetone-isopropyl ether being preferred.

The amount of saponifying agent employed is usually in excess of thattheoretically required to cause conversion of the 17(20) -oxido-20-enolester grouping to the lZ-hydroxy-ZO-keto grouping and to cause removalof the ester group at carbon atom three. Ratios of about fifty moles ormore of saponifying agent to one mole of the adduct are operative, withabout fifteen to twenty moles of saponifying agent to one mole of adductbeing preferred. If it is desired, one mole of saponifying agent to onemole of adduct may be used, in which case the ester group at carbon atomthree is not removed.

The starting 3,20-diacyloxy-9(1l) ,17(20)-dioxido-5,7-pregnadieneadducts have the formula:

wherein A and Ac have the values previously assigned.

The preparation of the starting 3,20-diacyloxy-9(11),17(20) -dioxido 5,7pregnadiene adducts involves oxidation of the corresponding 3,20diacyloxy 5,7,9(11),l7(20)pregnatetraene adduct using an organic peracidor hydrogen peroxide as the oxidant. Hydrogen peroxide is usuallyemployed in the form of a twenty to ninety percent by Weight aqueoussolution, a thirty percent solution being preferred. The reaction iscarried out by stirring the adduct and oxidant together, preferably inan organic medium which is nonreactive under the reaction conditions.Suitable media include chloroform, carbon tetrachloride, mixtures ofether and chloroform, glacial acetic acid, and many others. The ratio ofoxygen-furnishing agent to steroid can be varied considerably withinbroad ranges. Ratios of up to twenty moles to one are operative, butratios of from two to eight moles per mole of steroid are preferred forattainment of optimum yields, the exact ratio being preferably variedinversely with the reaction time desired to be employed. The temperatureof the mixture is usually maintained at from about zero degrees to aboutdegrees centigrade for a suitable period, e. g., from about one-half totwenty-four hours, depending on the concentration of oxygen-furnishingagent, and the 9(11) ,l'7(20) -dioxido compound then isolated in anyconvenient manner, such as by volatilizing the reaction medium,extracting the residue with chloroform, volatilizing the chloroform, andrecrystallizing the residue from an organic solvent.

Alternatively, the compounds may be recovered by pouring the reactionproduct into water, filtering the solution, and drying the precipitate.The dioxido compound is usually obtained in a state of high purity afterone or two recrystallizations. A convenient reaction medium when theoxidant is hydrogen peroxide is glacial acetic acid, and, when such isemployed, the dioxido compound is separated readily by pouring thereaction product onto cracked ice and extracting the 9(11)17(20)-di0xido compound with methylene chloride, evaporating to dryness,and recrystallizing the dried crude product, e. g., from isopropylether.

The adducts of 3,20-diacyloxy-5,7,9(11),- l7(20) -pregnatetraenes havethe formula:

(IJH: C-OAc OH? H dienophile selected from the group consisting ofmaleic acid anhydrideandmaleic acid diesters,

and wherein Ac has the value previously assigned. These compounds areconveniently. prepared by heating the corresponding 3-hydroxy or3-acyloxy-5,7,9(11) -pregnatrien-+one maleic acid, maleic acidanhydride, or maleic acid ester adduct with a large excess of an organiccarboxylic acid anhydridein the presence of a small amount ofthealkalimetal salt of the acid corresponding to the anhydride employed oran acid catalyst such as para-toluenesulfonic or sulfuric acid; Thepreferred anhydride is acetic anhydride, but other anhydrides, such aspropionic,

butyric, valeric, hexanoic, heptanoic, and octanoicanhydridesas well asbenzoic acid anhydride,ortho-toluic acid anhydride, and the like arealso operative. The acid anhydrides can also be: substituted bynon-reactive groups. such as halo, alkyl, and methoxy,.as.in the case ofchloroacetic, ortho-toluic, or methoxybenzoic acid anhydrides.Ordinarily the reaction is heated at about 140 degrees centigrade forfrom about fourto six hours, but temperatures as low as 100 and as. highas 180 degrees centigrade are also operative. The reaction is usuallyconducted at the boiling point of the anhydride, but in the case of thehigher-boiling anhydrides, such asbenzoic anhydride, a suitabletemperaturecontrol or or ganic solvent, preferably so as to maintain thetemperature between about 100 and 150 degrees centigrade, should beused, sincethe adduct otherwise tends to decompose in thehighertemperature range. If a 3-hydroxy 20.-keto adduct is thus reacted withan anhydride, the hydroxy group is usually acylated, and, similarly, ifa maleic acid adduct is used instead of a diester or an anhydride, theanhydride Will be formed. The enol ester can be isolated by removing theexcess anhydride under reduced pressure and separating the ester fromalkali metal salts,

which procedure gives aproductsufiiciently pure for most purposes, butwhich can be further puri- 1 fled by recrystallization fromacetone-water, acetone-pentane, or like solvents, if desired.

The 3-acyloxy-5,7,9(11) pregnatrien-20-one adducts are convenientlyprepared by the selective oxidation of an moi ester of an adduct of3-acyloxybisnor-5,7,9(11) cholatrien-22-al, represented by the formula:

acy1oirybisnor-5,7,9(11) cholatrien 22-al, of the formula: 1 3

H-CHO CH3 ACO V wherein A and Ac have the values previously given, tothe action of an acid anhydride or an acid halide in the presence of analkaline salt of the acid. The starting adducts of3-acyloxybisnor-5,7,9(11)-cholatrien-22- als can be 1 prepared fromadducts of S-esters of dehydroergosterol by selective oxidation asdescribed and claimed in the copending application Serial No. 111,100 ofRobert H. Levin, filed August 18, 1949, now Patent No. 2,620,337, issuedDecember 2, 1952, and as more fully described hereinafter.

The 3-esters of dehydroergosterol, from which the 3-acyloxybisnor-5,7,9(1l) -cholatrien-22-al adducts are prepared, can be synthesized inseveral ways starting with ergosterol. For example, ergosterol can betransformed to dehydroergosterol with mercuric acetate according toknown methods [Windaus et al., Ann. 465, 157 (1928)] and the 3-hydroxygroup of the dehydroergosterol acylated by known procedure.Alternatively the 3-hydroxy group of ergosterol can be acylated prior tothepreparation of the dehydro derivative, a procedure which isparticularly preferred in the preparation of the B-acetoxy derivative.The adducts of dehydroergosterol are then prepared by the addition ofmaleic anhydride or the like to dehydroergosterol or a 3-ester thereofaccording to known methods illonigmann, Ann. 508. 89 (1934)]. Theanhydrides can then be converted to their corresponding acids and estersif desired.

The ester group, when present in the 3-position of dehydroergosterol is.for the purpose of protecting the B-hydroxy group in. subsequentchemical reactions. For this purpose any convenient ester of an organiccarboxylic acid, which is non-reactive under the conditions of thereaction, is suitable. The. preferred acids are the fatty acids such asformic, acetic, propionic, butyric, valeric, hexanoic, petanoic,octanoic; dibasic acids such as malonic, succinic, phthalic;cycloaliphatic acids such as cyclopentanoic and cyclohexanoic; andaromatic acids such as benzoic, toluic, and the like. The acids may alsocontain substituents such as halogen, alkyl, the methoxy radical, andthe like, and these substituents will be carried throughout thesynthesis. If desired, the acyl group can be changed to another acylgroup by saponifying the ester to give a 3-hydroxy compound, which canthen be reesterified as previously described.

A preferred method for preparing some of the dehydroergosteryl adductscomprises the saponification of a B-acyloxy adduct of dehydroergosterolwith dilute alkali followed by acidification. The3-hydroxy dicarboxylicacid thus formed can be converted to the 3-hydroxy anhydride by heat, orit can be converted to a desired 3-acyloxy anhydride adduct by heatingunder reflux with the appropriate acid anhydride or chlo ride inpyridine solution. Dialkyl esters of the previously mentioneddicarboxylic acid adducts can be prepared by subjecting the acid to theaction of an esterification reagent such as a diazo alkane [Wilds etal., J. Org. Chem. 13, 763 (1948) l, e. g., diazomethane, diazoethane,diazobutane, and the like.

The selective oxidation of an adduct of dehydroergosterol, or a 3-esterthereof, to produce an adduct of3-hydroXybisnor-5,7,9(11)-chloratrien-22-al, or a 3-ester thereof, isaccomplished by dissolving the dehydroergosteryl adduct in a suitablesolvent, cooling to about minus eighty to plus thirty degreescentigrade, and passing ozone into the solution until about 1.0 to 1.25moles of ozone per mole of adduct have been absorbed. The temperature ofthe solution should be maintained below plus thirty degrees centigrade,preferably between a temperature of minus thirty and minus seventydegrees centigrade, during the addition of ozone, although temperaturesas low as minus eighty and as high as plus thirty degrees centigrade areoperative. The lower tern" peratures of the preferred range are readilyobtained by cooling the solution of the adduct with a bath of solidcarbon dioxide in acetone or the like, although various other methods ofcooling can be used. Many of the customary solvents used in ozonizationssuch as chloroform, acetic acid, carbon tetrachloride, ethylenechloride, methylene chloride, and the like, can be used.

The ozonides are then decomposed under reducing conditions, that is, inthe absence of oxidizing agents, whether added or formed in the courseof the reaction by products of decomposition of the ozonide. This meansthat excess oxygen formed by decomposition of the ozonide is preventedfrom forming hydrogen peroxide by combining with any moisture present,and that molecular oxygenis prevented from oxidizing the aldehyde thusformed. This can be conveniently accomplished by decomposing th ozonidein glacial acetic acid by the addition of finely-powdered zinc.

As is conventional with ozonizations when conducted in solvents, otherthan glacial acetic acid, the solvent used for ozonization is replaced,after completion of the ozonization, by adding glacial acetic acid andremoving the lower-boiling solvent by fractional distillation.Alternatively, the solvent can be removed by careful warming underreduced pressure prior to the addition of glacial acetic acid, ifdesired.

After decomposition of the ozonide and removal of the zinc, the aldehydecan be recovered by diluting the acetic acid with Water, or in otherconventional manner, such as by formation of an aldehyde derivative, e.g., the dinitrophenylhydrazone.

Adducts of 3,22diacyloxybisnor-5,'7,9(l1),20- 22) -cho1atetraenes[22-enol-esters of adducts of 3acyloxybisnor-Sflfi(11)cholatrien"22-als] can be conveniently preparedby heating the corresponding S-hydroxy or acyloxy aldehyde maleic acid,maleic acid anhydride, or maleic acid ester adduct with a large excessof an organic carboxylic acid anhydride in the presence of a smallamount of the alkali metal salt of the acid corresponding to theanhydride employed or an acid catalyst such as paratoluene sulfonic orsulfuric acid. The preferred anhydride is acetic anhydride but otheranhydrides, such as propionic, butyric, valeric, hexanoic, and octanoicanhydrides, as well as benzoic acid anhydride, orthotoluic acidanhydride, and the like, are also operative. The acid anhydrides canalso be substituted by non-reactive groups, such as halo, alkyl,

and methoxy, as in the case of chloroacetic, ortho-toluic, ormethoxybenzoic acid anhydrides, The reaction can be convenientlyfollowed by observing the color changes in the reaction mixture, optimumyields being obtained by discontinuing the application of heat when thecolor of the solution changes from yellow to brown. Ordinarily thereaction is heated at about degrees centigrade for from about four tosix hours, but temperatures as low as 100 and as high as degreescentigrade are also operative. The reaction is usually conducted at theboiling point of the anhydride, but in the case of the higher-boilinganhydrides, such as benzoic anhydride, a suitable temperature control,such as 100-150 degreescentigrate, must be used, since the adductotherwise tends to decompose in the higher temperature range. If a3-hydroxy aldehyde adduct is thus reacted with an anhydride, the hydroxygroup will be acylated, and, similarly, if a maleic acid adduct is usedinstead of a diester or an anhydride, the anhydride will be formed. Theenol ester can be isolated by removing the excess anhydride underreduced pressure and separating the enol ester from alkali metal salts,which procedure yields a product sufficiently pure for most purposes,but which can be further purified by recrystallization fromacetone-water, acetone-pentane, or like solvents, if desired.

The ozonization of the thus-prepared enol acylateto prepare3-acyloxy-5,'7,9(1l) -pregnatrien20one adducts involves dissolving theenol ester in a suitable solvent, cooling to about minus eighty degreescentigrade to plus thirty degrees centigrade, and passing ozone,ozonized air, or ozonizcd oxygen into the solution until about 1.0 toabout 1.25 moles, preferably 1.0 to 1.1 moles, of ozone per mole ofadduct have been absorbed. The addition of ozone to the 20:22 doublebond is so rapid that only a small amount of ozone escapes from thereaction mixture, and the amount of ozone ordinarily required thereforeclosely approximates the theoretical amount. Loss to the solvent, if anyloss occurs, must b taken into consideration in calculating the amountof ozone to be introduced. The temperature of the solution should bemaintained below plus thirty degrees centigrade, preferably between atemperature of minus thirty and minus seventy degrees centigrade, duringthe addition of ozone, although temperatures as low as minus eighty andas high as plus thirty degrees centigrade are operative. The lowertemperatures of the range are readily obtained by cooling the solutionof the adduct with a bath of solid carbon dioxide in acetone or thelike, although various other methods of cooling may be employed. Many ofthe customary solvents used in ozonizations, such as chloroform,methylene chloride. ethylene chloride, carbon tetrachloride, aceticacid, and the like, can be used for the ozonization reaction.

The 20:22 ozonides thus produced are then decomposed under conditionsnormally employed for decomposition of such compounds. This canconveniently be accomplished by decomposing the ozonide with hydrogenperoxide, by bydrolysis, with zinc in glacial acetic acid, or by acatalytic amount of colloidal metal such as silver, platinum, orpalladium in a solvent, such as glacial acetic acid, alcohol, or ethylacetate, in

which latter case reductive conditions, e. g., a hydrogen atmosphere,are also employed. The use of reductive conditions is Well establishedin the art [Hill and Kelly, Organic Chemistry,

page 53, The Blackiston Company, Philadelphia (1934).; Church et al., J.Am. Chem. Soc. 56, 176-184 (1934) Gilman Organic Chemistry, secondedition, page 636, John Wiley and Sons, New York (1943); Long, Chem.Reviews 27,

As is conventionalwith decomposition of ozonldes with zinc, whenthozonizations are conducted in solvents other than glacial actic acid,the solvent used for the ozonization is replaced,

after completion of the ozonization, by adding glacial acetic acid andremovin the lower-boiling solvent by fractional distillation, or thesolvent can be removed by careful warming under reduced pressure priorto the addition of acetic acid, if desired. After decomposition of the20:22 ozonide and removal of the metal, the

keton can be recovered by diluting the acetic acid with water, or byother conventional proce- PREPARATION 1.DI ETHrL MALEATE ADDUGT FDEHYDROERGOSTERYL BENZOATE To a solution of 21 grams of dimethyl maleateadduct of dehydroergosterol in 69 milliliters of warm pyridine was added9.5 milliliters of benzoyl chloride. After standing at room temperaturefor fifteen minutes, the mixture was poured into 1400 milliliters ofice-water and the solid removed by filtration, dried, and recrystallizedfrom acetone. There was thus obtained 26.4 grams of dimethyl maleateadduct of dehydroergosteryl benzoate, melting at 203 to 205.5 degreescentigrade.

PREPARATION 2.--DIMErrHYL MALEATE ADDUCT or DEHYDROERGOSTERYL ACETATE Ina manner essentially that described in Preparation l, the dimethylmaleate adduct of dehydroergosteryl acetate, melting at 177 to 179degrees centigrade, was prepared from the dimethyl maleate adduct ofdehydroergosterol and acetyl chloride.

PREPARATION 3.-DIMETHYL MALEATE ADDUCT 0F DEHYDROERGOSTERYL FORMATE Asolution of six grams of dimethyl maleate adduct of dehydroergosterol infifty milliliters of 87 percent formic acidwas heated under reflux forone hour, cooled, and the dimethyl maleate adduct of dehydroergosterylformate filtered therefrom. Upon crystallization from. acetone, thepurified material melted at 177.5 to 178.5 degrees centigrade.

PREPARATION 4.MALEIO ACID Annual or DEHYDROERGOSTELROL from adioxane-water mixture, the maleic acid 10 adduct of dehydroergosterolmelted at 190-192 degrees centigrade.

PREPARATION 5.MALEIC ANHYDRIDE ADDUC'I. or3-HEPTANOYLOXYDEHYDROERGOSTEROL The maleic acid adduct ofdehydroergosterol (9.2 grams, prepared as in Preparation 4) wasdissolved in a mixture of seven milliliters of warm pyridine andfourteen milliliters of heptylic anhydride, and the mixture heated underreflux for one hour. About eighty percent of the reaction solvent wasremoved under reduced pressure, and the residue then dissolved in methylalcohol. The methyl alcohol solution was concentrated and cooled toyield 4.8 grams of the maleic anhydride adduct of 3heptanoyloxydehydroergosterol, melting at 186-1915 degrees centigrade.

PREPARATION (it-Mannie ANHYDRIDE ADDUcT or 3 3- AGETOXYBISNOR-5,7 ,9(11) -CHOLATRDEIN-22-AL A solution of 5.35 grams of the maleic anhydrideadduct of 3B-acetoxydehydroergosterol in 107 milliliters of methylenechloride was cooled to about minus seventy degrees centigrade andozonized until 505 milligrams of ozone had been absorbed. Thetemperature of the solution was then gradually raised to about plus tento fifteen degrees centigrade. whereupon seventy milliliters of glacialacetic acid was added and the methylene chloride removed under reducedpressure. Seven grams of zinc dust was then added to the cold solutionat a uniform rate over a period of ten minutes, while keeping thereaction temperature below plus twenty degrees centigrade. After beingstirred for fifteen minutes, the mixture was filtered and the filtratepoured into water. There was thus obtained 4.31 grams of maleicanhydride adduct of 3,8-acetoxybisnor- 5,7,9(11)-cholatrien-22-al, afine white powder which melted at 187-197 degrees centigrade.

To a solution of 0.30 gram of the maleic anhydride adduct of3/3-acetoxybisnor-5,7,9(11)- cholatrien-ZZ-al, in thirty milliliters ofethanol, was added twenty milliliters of alcohol containing one percent2,4-dinitrophenylhydrazine and three percent concentrated hydrochloricacid. The mixture was allowed to stand for one hour at room temperatureand then placed in a refrigerator to complete precipitation of theyellow crystals. The precipitate was then collected and recrystallizedfrom a mixture of chloroform and alcohol, to give the2,4-dinitrophenylhydrazone of the maleic anhydride adduct of3,8-acetoxybisnor-5,7,9(11) -cholatrien-22-al, melting at 269- 271degrees centigrade.

PREPARATION 7.MALEIO ANHYDRIDE AuoUcT or 3/3- AUETOXYBISNOR-5,7 ,9 11-CHOLATRIEN-22-AL this rate the ozonizer was producing about 36milligrams of ozone per minute). The flow of ozonized oxygen wasmaintained for 128 minutes, a total of 4608 milligrams (105 percent) ofozone being passed into the solution. The reaction mixture wastransferred to a two-liter, roundbottom flask fitted with a capillaryand a condenser for downward distillation, 300 milliliters of aceticacid added, and the methylene chloride distilled over in vacuo at fortydegrees centigrade or below. The flask was then placed in a water bathand fitted with a stirrer. An additional 200 milliliters of acetic acidwas added and the ozonide decomposed by the addition of fifty grams ofzinc dust. The zinc dust was added in portions over a period of twentyto thirty minutes while the solution was stirred and the temperaturemaintained at seventeen to twenty degrees centigrade. After addition,the mixture was stirred for another twenty minutes and then filtered.The precipitated zinc dust was washed by filtering 108 milliliters ofacetic acid therethrough, and the filtrate gradually diluted with water(1100 to 1200 milliliters) until the product had been drowned out. Theproduct was then cooled in the refrigerator overnight and filtered. Theyield of crystalline product was 12 grams, assaying 89-95 percent of thedesired aldehyde.

PREPARATION 8 In a manner essentially that described in Preparation 6,the following compounds were prepared.

(1) Maleic anhydride adduct of3fl-formoxybisnor-5,7,9(i1)-cholatrien-22-a1, melting at 95- 130 degreescentigrade. 2,i-dinitrophenylhydrazone, melting at 165-168 degreescentigrade.

(2) Maleic anhydride adduct of 3fi-heptanoyloxybisnor-5,7,9(11)-cholatrien-22-al, melting at 197.5-199 degrees centigrade.2,4-dinitropheny1- hydrazone, melting at 258-257 degrees centigrade.

(3) Dimethyl maleate adduct of 3,8-benzoyloxybisnor-5,7,9(11)-cholatrien-22-al, melting at 183- 187 degrees Centigrade.2,4-dinitrophenylhydrazone, melting at 224-249 degrees centigrade.

(4) Dimethyl maleate adduct of 3/3-acetoxybisnor-5,7,9(ll)-cholatrien-22-al, melting at 172- 178 degrees centigrade.ZA-dinitrophenylhydrozone, melting at 238 to 244 degrees centigrade.

(5) Dimethyl maleate adduct of 3-hydroxybisnor-5,7,9 (11)-cholatrien22-al, melting at 163- 170 degrees Centigrade.2,4-dinitrophenylhydrazone, melting at 250-25 1 degrees centigrade.

In a manner similar to the above, the maleic anhydride adduct oi3-hydroXybisnor-5,7,9(l1)- cholatrien-ZZ-al is obtained fromdehydroergosteryl maleic anhydride adduct; the maleic acid adduct of3-hydroXybisnor-5,7,9 (11) -cholatrien- 22-al is obtained fromdehydroergosteryl maleic acid adduct; and 3-acyloxybisnor-5,7,9(11)cholatrien-22-al maleic acid adducts are obtained from the maleic acidadduct of 3-acyloxydehydroergosterols.

PREPARATION 9.D1METHYL liIALEArE ADDUGT or 8- HYDRoXYBIsNoR-iS,7,9 (11)-oHoLArR1EN-22-AL zinc dust was added in portions with stirring, the

temperature being maintained between fifteen and twenty degreescentigrade. Stirring was continued for another fifteen minutes,whereafter the Zinc was separated by filtration, the filtrate wasdiluted with water to cloudiness, extracted with ether, the etherextract washed with sodium bicarbonate and then with water toneutrality,

l 186 to 193 degrees centigrade.

the solution then dried over sodium sulfate and evaporated to dryness invacuo. The residue was crystallized from acetic acid and water, giving1.92 grams (81.5 percent of the theoretical) melting point 91-97 degreescentigrade, which yielded a dinitrophenylhydrazone derivative in 72.5percent yield, melting point 212-238 degrees centigrade. The 'aldheydewas recrystallized and found to have a purified melting point of 163-170degrees centigrade, while the dinitrophenylhydrazone derivative wasrecrystallized until a melting point of 250-25 1 degrees centigrade wasattained.

PREPARATION 10.IVIALEIC ANHYDRIDE ADDUor OF 313- ACETOXY 22ACETOXYBISNOR 5,7,9(11),20(22) CHO'LATETRAENE A mixture of twenty gramsof the maleic anhydride adduct of 3,8 acetoxybisnor 579(11)-cholatrien-22-al, six grams of anhydrous sodium acetate, and 600milliliters of acetic anhydride, was heated under reflux for six hours,whereafter volatile components were removed under reduced. pressure. Theresulting solid was digested with five fifty-milliliter portions ofboiling acetone for five minutes each, and the extracts combined anddiluted with 130 milliliters of water. There was thus obtained sixteengrams of the maleic anhydride adduct of 3c-acetoxy-22-acetoxybisnor-5,7,9(11),20 22)-cholatetraene, which melted at Recrystallization of thecrude product from a mixture of acetone and pentane raised the meltingpoint to200.5 to 202 degrees centigrade.

PREPARATION 11 In a manner essentially that described in Preparation 10,the following compounds were prepared:

(1) The dimethyl maleate adduct of 313-benzoyloxy 22 acetoxybisnor5,7,9(1l),20(22)- oholatetraene, which melted at 210 to 211 degreescentigradc.

(2) The dimethyl maleate adduct of 3fi-acetoxy 22acetoXybisnor-5,7,9(l1) ,20(22 -cholatetraene, which melted at 181 to183 degrees centigrade.

In the same manner as given above, 22-acyloxy, e. g., iormoxy, acetoxy,propionoxy, butyroxy, valeroxy, hexanoyloxy, heptanoyloxy, octanoyloxy,benzoyloxy, naphthaoyloxy, and the like 3-acyloxybisnor-5,7,9 1 1) ,20(22) cholatetraene adducts, are obtained from the compounds ofPreparations 6, 7, and 8. Such representative compounds include3-formoXy-22-acetoxybisnor- 5,7,9(11) ,20 (22) -cholatetraene,3-propionxy-22- acetoxybisnor 5,7,9(11) ,20 22) cholatetraene, 3,22dipropionoxybisnor-5,7,9(11) ,20(22) -cholatetraene, 3,22dibenzoyloxybisnor 5,7,9(l1) ,20- (22) -cholatetraene, and3heptanoyloXy-22-octanoyloxybisnor 5,7,9(11),20(22) cholatetraeneadducts with maleic anhydride or maleic acid esters such as the dimethylmaleate, diethyl" maletate, dipropyl maleate, diisopropyl maleate,

dibutyl maleate, 'dioctyl maleate, dibenzyl maleate, and the like.

PREPARATION 12-.-MALE1o ANHYDRIDE Aoouor or 3/3- AoEToXY-5,7,9 (11)-PREGNATRIEN-20-ONE A solution of 5.08 grams of the maleic anhydrideadduct of 3fi-acetoxybisnor-5,7,9(11)- cholatrien-ZZ-al enol acetate inmilliliters of methylene chloride was cooled to about minus seventydegrees centigrade and ozonized until 483 milligrams of ozone had beenabsorbed. Fifty milliliters of glacial acetic acid was then 13 added andthe methylene chloride removed under reduced pressure. An additionalthirty milliliters of glacial acetic acid was then added and the ozonidedecomposed by adding seven grams of powdered zinc at a substantiallyuniformrate while maintaining the reaction temperature between seventeenand twenty degrees centigrade. The mixture was stirredfor an additionaltwenty minutes, filtered, and the zinc washed with 140 milliliters ofglacial acetic acid. The organic extracts were combined and diluted withseventy milliliters of water. When crystallization commenced, the rateof precipitation was increased by addition of two volumes of Water.There was thus obtained 4.0 grams of the maleic anhydride adduct of 33-acetoxy-5,7,9(1l)-pregnatrien-20-one, which melted at 240-2645 degreescentigrade. .Several recrystallizations of the crude material fromacetone raised the melting point .to 263.5 to 1 264.5 degreescentigrade.

PaneARATIoN 13.--MALEIO A011) ADDUCT 01? 3,8- HYDRoxY-5,7 ,9 (11)PBEGNATRIEN-20'-ONE A solution of 4.52 grams (0.0100 mole) of the maleicanhydride adduct of 3B-acetoxy-5,7,9(1l) pregnatrien-20-one, M. P.263-2645 degrees centigrade, in a mixture of 100 milliliters of 1,4-

dioxane and 400 milliliters of water containing four grams (0.10 mole)of sodium hydroxide was allowed to stand at room temperature for two andone-half hours, whereupon a small quantity of plate-like crystalsformed. These were dissolved by heating the mixture to seventy degreescentigrade for one-half hour. The reaction mixture was then made acidwith fifty milliliters of three normal hydrochloric acid andrefrigerated to give a precipitate of 3.05 grams of needle-like crystalsmelting at 173-177 degrees Centigrade.

On crystallization from a dioxane-water mixture,

PREPARATION 14.DIiuErHYn MALEA'rm ADDUCT on 3,8- HYDROXY5,7 ,9 (11)-PREGNATRDEN-20-ONE A suspension of 0.400 gram of the maleic acid adductof 35-hydroxy-5j7 ,9 (11) -pregnatrien-20- one, in fifty milliliters ofdry ether, was cooled in an ice-salt bath While a slight excess ofdiazomethane in methylene chloride was added over a 25-minute periodwith stirring. Ten minutes after addition was complete, the solution wasplaced on a steam bath and concentrated rapidly to dryness. The residuewas crystallized from an acetone-water mixture to give 0.34 gram of thedimethyl maleate adduct of 3 3-hydroxy- 5,7,9(11) -pregnatrien20-one,melting at 193-195 degrees centigrade. After chromatography andrecrystallization, the compound melted at 192-197 degrees centigrade.

In the same manner as given above, other dialkyl maleates, e. g., thediethyl, dipropyl, diisopropyl, dibutyl, and dioctyl maleates of3-hydroxy-5,7,9(11) -pregnatrien-20-one are prepared from3-hydroxy-5,7,9 (11) -pregnatrien-20- one maleic acid adduct and theappropriate diazoalkane, or by other equivalent esterificationprocedure. 1

PREPARATION l5.DIMETHYL MALEATE Annndr OF 3,8- AoEroxY-5,7,9 (11)-PREGNATRIEN-20-QNE A solution of 0.15 gram of the dimethyl maleateadduct of 3B-hydroxy5,7,9(1l)-pregnatrien-20- one, in 2.5 milliliters ofacetic anhydride and 2.5

milliliters of pyridi'r'le, was heated on the steam bath for ninety:minutes, cooled to room tem perature, and pouredintoice-water. Theresulting precipitate was collected by filtration and found to melt at205-209degrees centigrade. Recrystallization from methanol give thedimethyl maleate adduct of 3fi-acetoxy-5,7,9(l1)- pregnatrien-ZO-one,melting at 207-211 degrees Centigrade.

Analysis-Percent calculated for 029113807: C, 69.86; H, 7.68. Found: C,69.81; H, 7.86; C, 69.70;H, 7.62. i

By the same manner of esterification, the following C-3 esters wereprepared: (1) dimethyl maleate adduct of 38-formoxy-5,7,9(ll)-pregnatrieh-ZO-one, melting point 223-230 degreescentigrade, and (2) the dimethyl maleate adduct of3fl-benzoyloxy-5,7,9(11) -pregnatrien-20-one,

melting point 250-254 degrees centigrade.

PREPARATION 16.-MALnrc ANHYDRIDE ADDUCT or 3 8- HEPTANoYLoxY-5J ,9 (11)-PBEGNATRIEN-20-0NE PREPARATION 17.MALEro ANHYDRIDE AnDUo'r OF 35-HYDROXY5,7 ,9 (11) -PBEGNATR1EN-20-0NE Similarly, the maleic anhydrideadduct of 3B- hydroxy-5,7,9(11) -pregnatrien 20 one, melting point aboutdegrees centigrade, was prepared by refluxing the maleic acid adduct of3fl-hydroxy-5,7,9(l1) -pregnatrien-20-one with 1 Dow therm for eighthours. The 3-hydroxy-maleic anhydride adduct is also obtained by heatingthe 3-hydroxy maleic acid adduct to just above its melting point, whichprocedure causes water tosbe evolved, with the closing of the anhydridering.

In the same manner as given above, still other 5,7,9(11)-pregnatrien-20-one adducts are prepared from the corresponding3,22-diacycloxybisnor 5,7,9(l1),20(22) cholatetraene maleic acidanhydride, and maleic acid diester adducts. Such compounds include the 3formoxy- 5,7,9(11) -pregnatrien-20-one maleic acid, maleic acidanhydride, dimethyl maleate, diethyl maleate, dibutyl maleate, dioctylmaleate, diisopropyl maleate, dibenzyl maleate, and like adducts; thecorresponding 3-propionoxy, butyroxy, valeroxy, hexanoyloxy,heptanoyloxy, octanoyloxy, napthtlioyloxy, benzoyloxy, andsimilarZO-ketone adducts, including, for example 3-propionoxy-5,7,9 (l1)-pregnatrien-20-one dipropyl maleate, 3-

benzoyloxy-5,7.9(l1) -pregnatrien-20-one maleic I anhydride adduct,3-heptoyloxy-5,7,9(l1)-pregnatrien-20-o-ne dimethyl maleate,3-valeroyloxy- 5,7,9(11)-pregnatrien-20-one maleic acid anhydrideadducts, and the like.

PREPARATION l8.-MALnro ANHYDRIDE ADDUCT or 3]3,20-DIAOETOXY-5,7,9 11),17 (20 -PREGNATETRAENE (1) The dimethyl maleate adduct of3B,20-diacetoxy-5,7,9 11) ,17 (20) -pregnatetraene, having a doublemelting point of 116-119 degrees and 1 164-168 degrees centigrade.

AnaZysis.-Percent calculated for CIllH lOOBI C, 68.86; H, 7.46. Found:C, 69.04; H, 7.69; C, 68.71; H, 7.80.

(2) The dimethyl maleate adduct of 3B-acetoxy 20 propionoxy5,7,9(11),17(20) pregnatetraene having, by infrared spectroscopy, anabsorption peak in the ester'region at 1742 cancharacteristic of theC=C-O acyl grouping; and having lost the strong carbonyl absorption at1700 cm.- of the starting -20 ketone.

In the same manner as given above, other 3,20-diacyloxy-pregnatetraeneadducts including 3,20 dipropionoxy 5,7,9(1l),17(20) pregnatetraenemaleic anhydride adduct, 3-acetoxy-20- propionoxy 5,7,9(11),l7(20)pregnatetraene maleic anhydride adduct, 3-octanoyloxy octanoyloxy5,7,9(11),17(20) pregnatetraene dimethyl maleate adduct,3-benzoyloxy-20-acetoxy-5,7,.9(11), l7(20)-pregnatetraene maleicanhydride adduct, 3-butyroxy-20-benzoyloxy-5,7,9 l1 ,17 (20)-pregnatetraene maleic adduct, 3 iormoxy 20 acetoxy 5,7,9(11),l7(20)-pregnatetraene dimethyl maleate adduct, 3,20 dibutyroxy5,7,9(1l),l7(20) pregnatetraene diloutyl maleate adduct, and the like,are prepared.

PREPARATION 20. 3B,20-DIACETOXY-9(11) ,17 (20)-1 1-OKIDO-5,'T-PREGNADIENE DIMETHYL MALEATE AnoUo-r In a 500 milliliterErlenmeyer flask is dissolved 5.35 grams of3B,20-diacetoxy-5,7,9(ll),17(20)- pregnatetraene maleic acid dimethylester adduct in 220 milliliters of acetic acid. To this solution isadded a solution of 22 milliliters of thirty percent hydrogen peroxidein 75 milliliters of acetic acid. The resulting solution is heated onthe steam bath for four hours and allowed to cool at room temperatureovernight. It is then poured into 2000 grams of crushed ice andextracted, after the ice has melted, with three 300 milliliter portionsof methylene chloride. The methylene chloride solution is washed withwater, dried over anhydrous sodium sulfate, and evaporated to dryness invacuo. The residue is dissolved in acetone, an equal amount of isopropylether is added, and the solution concentrated on the steam bath untilcrystallization starts. Upon cooling and filtering, the yield is 2.95grams, melting at 236-240 degrees centigrade. After severalrecrystallizations from the same solvent, the melting point is raised to270- 272 degrees centigrade. This material appears to be a mixture ofisomeric compounds of different melting points.

anhydride PREPARATION 21. Sp,20-DIAcnToxY-9(11) ,17(20)-D1- OXIDO5,7-PREGNADIENE MALEIo ANHYDRIDE ADDUCT To a solution of 3. grams of themaleic anhydride adduct of 3,20 diacetoxy 5,7,9(ll), 17(20)-pregnatetraene in milliliters of acetic acid is added a solution of 6.2milliliters of thirty percent hydrogen peroxide in forty milliliters ofacetic acid. The mixture is heated on the steam bath for 3.5 hours,allowed to stand at room temperature overnight, and poured over 500grams of crushed ice. The resulting solid (2.28 grams, M. P. -217degrees centigrade (is twice recrystallized from methanol to give 0.81gram of 3,20 diacetoxy 9(l1),l7(20) dioxido 5,7- pregnadiene maleicanhydride adduct, melting at 239-250 degrees centigrade.

PREPARATION 22.-3,8-ACETOXY-QU-IFROPIONOXY- 9(11),17 (20) DIOXIDO5,7-PREGNADIENE DI- METHYL MALEATE ADDUCT PREPARATION 23.3-BENZOYLOXY-20-ACETOXY- 9(11),17(20)-DI0XIDE-5,7 PREGNADIENE MA- LEIOANHYDRIDE ADDUCT This compound is prepared in the manner of the threepreceding preparations, using hydrogen peroxide in a glacial acetic acidmedium, from 3 benzoyloxy 20 acetoxy 5,7,9(l1), 17(20) pregnatetraenemaleic anhydride adduct, which is prepared in the manner of Preparation18.

In the same manner as given above, other 3,20- diacyloxy-9 11) ,17 (20)-dioxido-5,7 pregnadiene adducts are prepared, including 3,20-dipropionoy-9 11) ,17 (20) -dioxido-5,7-pregnadiene male c anhydride adduct,3-acetoxy-20-butyroxy 9(11) i7 (20) -dioxido-5,7-pregnadiene maleicanhydride adduct, 3-octanoyloxy-20 octanoyloxy 9(11),17(20)-dioxido-5,7-pregnadiene diootyl maleate adduct,3-benzoyloxy-20-acetoxy 9(1l),17(20)- dioxide-5,7-pregnadiene diethylmaleate adduct, 3-butyroxy 20 acetoxy 9(11),17(20)-dioxido5,7-pregnadiene maleic anhydride adduct, 3-formoxy-20-acetoxy-9(ll),l7(20) dioxide 5,7- pregnadiene dimethylmaleate adduct, 3,20-dibutyroxy-9(ll) ,17 (20) -dioxido-5,7 pregnadienedibutyl maleate 'adduct, and the like.

In the same manner as given above for the anhydride adduots, thediacyloxy dioxide maleimide and N-alkylmaleimide adducts are preparedfrom the corresponding 3,20 diacyloxy 5,7,9(11) ,17- (20)-pregnatetraene adducts.

Example 1.-3,8,17-dihydroa:y-9(11) oxide 5,7-

pregnadien-20-one dimethyl maleate adduct To a solution of 1.2 grams of35,20-diacetoxy- 9(ll),17(20)-dioxido 5,7 pregnadien dimethyl maleateadduct in sixty milliliters of methanol was added 2.5 grams of sodiumhydroxide in five milliliters of water. The mixture was allowed to standat room temperature for one hour and was then drowned out with water andextracted with ether and with methylene chloride. The extracts werewashed with water, dried over anhydrous sodium sulfate, and evaporatedto dryness under reduced pressure. The residue was crystallized Eza'mple2.3e-acetomy 9(11) oxide-17 hydromy-5,7-pregnadien-20-o'ne dimethylmaleate adduct 35,17-dihydroxy-9-(11) oxido 5,7 pregnadien-20-onedimethyl maleate adduct (0.26 gram) was dissolved in five milliliters ofpyridine and five milliliters of. acetic anhydride and allowed to standat room temperature overnight. The solution was then poured intoice-water and the resulting crystalline product, 0.2 i gram, whichmelted at 242-246 degrees centigrade, collected. Recrystallization fromacetone-isopropyl ether gave pure 3e-acetoxy-9(1l)-oxido-17 hydroxy-5,7-pregnadien-20-one dimcthyl maleate adduct, melting at 246-248degrees. ,centigrade; [111 plus 45.1 degrees (chloroform).

AnaZysis.-Per cent calculated for CzsHssOsl C, 65.64; H, 7.22. Found: C,66.20; H, 7.15.

The same product is produced by careful saponification of 35,20diacetoxy-9(1l) ,17(20) -di oxido-5,7-pregnadiene dimethyl maleateadduct with sodium hydroxide in the ratio of one mole of sodiumhydroxide to one mole of adduct.

Example 3.--3e beneoyloacy-QUI -oxido-17-hy-' droxy5,7-pregnadien-20-one dimethyl maleate adduct Following the proceduregiven in Example 2, 3B-benzoy1oXy-9(11)-oxido 17 hydroxy 5,7-pregnadien-ZO-one dimethyl maleate 'adduct is prepared by benzoylationof 3s, 17-dihydroxy- 9(11) -0xido-5,7 pregnadien 20 one dimethyl maleateadduct with benzoic anhydride and py-tridine or by carefulsaponification of 3fl-benzoyloxy-20-acetoxy-9(l1) ,17(20) dioxide5,7-pregnadiene dimethyl maleate adduct which is prepared from 35benzoyloxy 20 acetoxy 9(11), 17 (20) -diOXidO-SJ-pregnadienemaleicanhydride adduct by esterification with diazornethane.

Example 4 .-3,;3,1 7 -dihydro;c11-9 (1 1) -0xido- 5 ,7 pregnadien-ZO-onc maleic acid adduct Following essentially the procedure given inExample l, 35,20 diacetoXy-9(ll) ,l7(20 -dioxido- 5,7-pregnadiene maleicanhydride adduct is allowed to react with an excess of sodium hydroxideto give 343,17 dihydroxy 9(1l)-oxido5,7pregnadien-20-one maleic acidadduct.

Example 5.-3e,17-dihydro-zcy-9(11) orido 5,7-

pregnadien-ZO-one maleic anhydrz'de adduct Example 6.--3/3-aceto.ry9(11) oosido 17 hydroxy-5,7-pregnadien-20-one maleic anhydride adductFollowing the procedure given in Example 2, 3,8,1? dihydroxy-Q (11)-oxido-5,7-pregnadien-20- one maleic anhydride adduct is acetylated with18 acetic anhydride' and pyridine to yieldlo-acetoXy-Q(ll)-oxido-l7ahydrcxy 5,7 pregnadien- 20-one maleicanhydride adduct.

The same compound, 3fl-acetoxy-9(i1l)-oxido-17-hydroxy-5,7-pregnadien-ZO-one maleic anhydride adduct, is preparedfrom 3 3,17-dihydroxy- 9(11)-oXido-5,7pregnadien 20 one maleic acidadduct by reaction with acetic anhydride and pyridine according to theprocedure of Example 2, which procedure, in addition to causingacetylation at the 3-position,.causes elimination of water from the acidadduct to. form the anhydride adduct.

According to the procedure given in Examples 2 and 6, other carbon atomthree esters are prepared, the ester being limited only by the choice ofesterifying agent used}; Such compounds include the maleic anhydride anddimethyl maleate adducts of 3 propionoxy 9(11) oxido l7-hydroxy-5,7pregnadien 20-one, 3 butyroyloxy-9(11)-oxido-17-hydroxy-5,7-pregnadien-20 e one, 3-va1eroy1oxy 9-(11)oxido 1'7 hydroxy-5,7- pregnadien-ZO-one, 3 hexanoyloxy-9 (11) -oxido-17 hydroxy 5,7 pregnadien 2'0 one, 3-heptanoyloxy 9 (11) oxide 17hydroxy-5,7-pregnadiene-20-one, 3 octanoyloxy-QGI) -oxido-17- hydroxy5,7 pregnadien 20 one, and the like.

It is to be understood that the invention is not to be limited to theexact details of operations or exact compoundsshown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 9(11) oxido 17- hydroxy 5,7 pregnadiene-ZO-one adduct represented bythe formula:

wherein Ac is selected from the group consisting of hydrogen and theacyl radical of hydrocarbonmonocarboxylic acid containing from one toeight carbon atoms, inclusive, and wherein A is the adduct radical. of adienophile selected from the group consisting of maleic acid, maleicanhydride, and maleic acid lower-alkyl diesters, wherein the lower-alkylgroups contain from one to eight carbon atoms, inclusive.

2. 3,17 dihydroxy 9(11) o-xido 5,7 pregnadiene-20-one dimethyl maleateadduct.

3. 3 acetoxy 9(11) oxido 17 hydroxy- 5,7-pregnadiene-20-one dimethylmaleate adduct.

d. 3 bonzoyloxy 9(11) oxido l7 hydroxy-5,7-pregnadiene20-one dimethylmaleate adduct.

5. 3,17 dihydroxy 9(11) oxide 5,7 pregnadiene-20-one maleic anhydrideadduct.

6. 3 acetoxy 9(11) oxide 17 hydro-xy- 5,7-pregnadiene-20-one maleicanhydride adduct.

7. A process for the production of a 9(l1)-oxido-17-hydroxy-5,7-pregnadiene-20-one adduct which includes the stepof mixing together 19 a 3,20-diacyloxy-9(11) ,17(20)-dioxido-5,7-pregnadiene adduct of the formula:

wherein Ac is the acyl radical of an organic carboxylic acid, andwherein A is the adduct radical of a dienophile selected from the groupconsisting of maleic anhydride and maleic acid diesters, with analkali-metal hydroxide, at a reaction temperature between about zero andsixty degrees centigrade, and separating from the reaction product the9(11) -oxido-1'7-hydroxy-5,'7- pregnadiene-ZO-one adduct thus produced.

8. A process for the production of a 9(1l)-oxido-l'l-hydroxy-5,7-pregnadiene-20-one adduct which includes the stepof mixing together a 3,20-diacyloxy-9(11) ,17(20)-dioxido-5,7-pregnadiene adduct of the formula:

CH: -OAc O OH:

AcO

wherein Ac is the acyl radical of an organic carboxylic acid containingup to and including eight carbon atoms, and wherein A is the adductradical of a dienophile selected from the group consisting of maleicanhydride and maleic acid lower-alkyl diesters wherein the lower-alkylgroups contain from one to eight carbon atoms, inclusive, with sodiumhydroxide, at a reaction temperature between about zero and sixty de-:

grees centigrade, and separating from the reaction product the9(11)-oxido-17-hydroxy-5,7- pregnadiene-ZO-one adduct thus produced.

9. A process for the production of 3,1'7-dihydroxy-9 (11)-oxido-5,7-pregnadiene-20-one dimethyl maleate adduct which includesmixing together a 3,20-diacyloxy-9(ll) ,17(20) -dioxi'do-5,7-pregnadiene dimethyl maleate adduct of the formula:

A Ac0 J wherein A0 is the acyl radical of an organic carboxylic acidcontaining up to and including eight carbon atoms, and wherein A is thedimethyl maleate adduct radical, with sodium hydroxide in the ratio ofbetween two and twenty moles of sodium hydroxide to one mole of startingadduct, at a reaction temperature between about zero and sixty degreescentigrade, and separating from the reaction product 3,17-dihydroxy-9(11) oxido-5,7-pregnadiene-20-one dimethyl maleate adduct.

10. A process. for the production of 3,17-dihydroxy- (11)-oxido-5,7-pregnadiene-20-one dimethyl maleate adduct which includesmixing together 3,20 diacetoxy 9(11) ,1'7(20) dioxido- 5,7-pregnadienedimethyl maleate adduct with sodium hydroxide in the ratio of betweenabout two and about twenty moles of sodium hydroxide to one mole ofstarting adduct, at a reaction temperature between about zero and sixtydegrees centigrade, and separating from the reaction product3,1'7-dihydroxy-9(11)-oxido--5,7- pregnadiene-ZO-one dimethyl maleateadduct.

No references cited.

1. 9 (11) - OXIDO - 17- HYDROXY - 5,7 PREGNADIENE-20-ONE ADDUCTRESPECTED BY THE FORMULA: